Optiuni de Tratament in Eczema PDF

JEADV
DOI: 10.1111/j.1468-3083.2010.03615.x
ORIGINAL ARTICLE
Redefining treatment options in chronic hand eczema (CHE)

Robert Bissonnette, Thomas L. Diepgen, Peter Elsner, John English, Robin Graham-Brown,
Bernhard Homey, Thomas Luger,,* Charles Lynde, Jurgen Maares, Howard I. Maibach
Innovaderm Research, Montreal, QC, Canada

Department of Social Medicine, Occupational and Environmental Dermatology, University Hospital of Heidelberg, Heidelberg,
Germany
Friedrich Schiller University, Jena, Germany
Queens Medical Centre, Nottingham, UK
University Hospitals of Leicester, Leicester, UK
Heinrich-Heine-University, Dusseldorf, Germany
University Clinics Munster, Munster, Germany
Lynderm Research, Markham, ON, Canada
Basilea Pharmaceutica International Ltd, Basel, Switzerland
University of California, San Francisco, CA, USA

*Correspondence: T Luger. E-mail: derma@uni-muenster.de
Introduction
Professor T. Luger
Chronic hand eczema (CHE) is not a uniform disease. Differences in aetiology, morphology and severity make accurate diagnosis difficult, further hampered by the lack of a systematic
classification system. Until now, patients with severe CHE have
had few treatment options available to them if topical corticosteroids have failed to improve their situation. This supplement,
based on a standalone meeting that took place in Paris, is a
collection of presentations given by an internationally renowned
panel of experts in CHE, covering every aspect of the disease
and its treatment. It also captures questions raised by the audience during that meeting and makes this extensive summary the
most comprehensive and up-to-date synopsis of current thinking
within CHE.
The first part looks at current understanding of the disease,
difficulties in diagnosis and the need for a systematic classification
system to improve patient outcomes. This is followed by a discussion on the role of the skin barrier and how, by using the full range
of investigative methods available to dermatologists and comprehensively documenting skin barrier function, the aetiology of CHE
can be better understood. Then two sections follow on the impact
of CHE on both society and the patient to capture on one hand
the social, occupational and economic burden of CHE, and on the
other hand, what it means for the patient to live on a daily basis
with such a chronic and relapsing disease. The second part of the
supplement presents the benefits and limitations of current treatment options, including topical and systemic therapies. It reflects
current treatment paradigms, and the clinical evidence supporting
them. The pharmacology of alitretinoin an endogenous vitamin
A derivative and, an emerging systemic treatment for the manage-
JEADV 2010, 24 (Suppl. 3), 120
ment of severe CHE is introduced in the following section. This

is followed by a discussion on the proposed mode of action of
alitretinoin and its interference at different steps in the immune
and inflammation processes within the skin. Clinical data are then
presented from the Benefit of Alitretinoin in Chronic Hand
Eczema (BACH) study, the largest controlled trial in CHE to date,
and a retreatment study demonstrating that patients who previously achieved clear or almost clear hands during the BACH study
also responded to a second course of treatment, allowing for intermittent long-term treatment of this chronic disease. Combined
safety data from the large alitretinoin phase III clinical trials complete this section. The third part of the supplement concludes by
assessing methods of advancing CHE management in clinical practice using evidence-based medicine (EBM), and the development
of much-needed treatment guidelines. It also includes a short section aimed at providing answers to some of the commonly asked
questions on alitretinoin usage in a daily clinical practice.
Understanding CHE and its impact

on society and the individual
patient
Understanding the disease, diagnosis
and classification
Professor T. L. Diepgen
Hand eczema prevalence, epidemiology and

aetiology
Hand eczema (HE) is the most common skin disorder affecting
the hands. In a substantial number of patients, HE can develop
into a chronic condition, with disease remaining active even after
2010 The Authors

Journal compilation 2010 European Academy of Dermatology and Venereology
contact with potentially damaging allergens and or irritants has

been avoided.1 CHE has been defined as either a long-lasting,
relapsing course of HE, or HE unresponsive to standard treatment
with emollients and topical corticosteroids. It is estimated that 5
7% of HE patients have severe CHE, and 24% are unresponsive
to standard treatment.2
Hand eczema is not a uniform disease and varies because of differences in aetiology, morphology and severity. About 50% of HE
patients seek some form of dermatological treatment and 5% of
HE patients are on sick leave at any given time.2 Prevalence rates
account for up to 30% of HE amongst specific, high-risk, occupational groups involved in wet work, or exposed to irritant and or
allergic substances (such as hairdressers, cooks, cleaners, healthcare
workers, etc.).3 Some studies have shown a higher incidence of HE
in female patients, which is most likely because of environmental
factors.2 Atopy is also a risk factor for HE.4,5 It has been estimated
that 7080% of childhood eczema is because of an inherited allergic susceptibility, and amongst those with childhood eczema, a
threefold increase in the risk of HE has been observed.5 Exposure
to environmental factors, such as skin allergens or irritants, and
endogenous factors, such as atopy, play interrelated roles in the
aetiology of HE. It is rarely possible to identify all causative factors
and remove them entirely.2,6,7
Hand eczema has a poor long-term prognosis. In a 15-year follow-up study, patients diagnosed with HE were questioned concerning the persistence and course of their disease.8 Of the 868
patients who answered the questionnaire, 66% reported periods of
HE during the preceding 15 years, 44% reported symptoms during
the previous 12 months, 12% reported continuous eczema and 3%
of those who were gainfully employed during the original study in
1983, reported a change in occupation because of their HE (15 of
these reported improvement after the job change). The study
found that risk factors associated with a poor long-term prognosis
included the extent of eczema involvement at initial examination,
a history of childhood eczema and onset of HE prior to the age of
20.8 All of these individual factors significantly influenced the total
time suffering from HE during the previous 15 years and the
occurrence of HE in the immediately preceding year. Patients with
all three risk factors had twice the chance of still having HE after
15 years compared with patients with none of the risk factors.8
Classification and morphology

There is currently no universally accepted classification for HE,
and most published classifications invoke a combination of aetiological factors (irritant, allergic and atopic disease) and morphological features such as hyperkeratotic or vesicular (dyshidrotic,
pompholyx) eczema. No existing system completely accounts for
the existence of hybrids and combinations of the various morphological categories, or overcomes the inability to determine aetiology in a high proportion of cases.
Agreement on a classification system for the subtypes of HE will
be an important step in improving outcomes for patients suffering
JEADV 2010, 24 (Suppl. 3), 120
from this debilitating condition by facilitating earlier and more

accurate diagnoses, and hence, more effectively targeted therapy.
Diagnosis
Given these limitations, accurate diagnosis of the disease is challenging and should be initiated by taking a full and careful medical
history. Patients should be questioned about their previous HE
history, particularly that relating to the type of lesions and the
time courses of both flares and remitting periods. The morphology
and location of the lesions must be examined as this will help
exclude differential diagnosis with psoriasis, and infections or
other causes must be excluded. Patch tests, guided by occupational
and leisure time history, should be considered as a mandatory
step. Positive patch-test findings require specialist interpretation
with regards to relevance to current disease activity of CHE.
Chronic hand eczema

In a substantial number of HE patients, the disease develops into a
chronic condition even when an initial causative agent is avoided.2
Particularly in the case of occupational dermatoses, allergic and
irritant contact dermatitis usually appears to precede the development of a more chronic condition. It is possible that the inflammatory changes in the skin increase the likelihood of acquiring a
secondary allergy the second stage in a long series of events. Sensitization may possibly be allayed by offering preventative measures
at the point where irritant contact dermatitis starts, thereby preventing the sequelae which may follow. Clinical signs and symptoms of CHE comprise classic features of eczema localized to the
hands, including erythema, oedema, hyperkeratosis, scaling, lichenification, vesiculation blistering, fissures, pruritus and pain.912
The role of the barrier function in CHE

Professor H. I. Maibach
Impaired skin barrier function is a key factor in eczema. Skin barrier function can be impaired by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme, a
protease enzyme that causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The
addition of environmental interactions or long-term application of
topical corticosteroids can further increase production of stratum
corneum chymotryptic enzyme and impair epidermal barrier
function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus.
Defective skin barrier function increases the risk of penetration of
irritants and allergens through the skin. This initiates immunological reactions and inflammation.
It is possible that all of the disease subtypes loosely called hand
eczema syndrome have differently impaired skin barrier functions,
and, given the lack of agreement on their disease morphology, we
2010 The Authors

need to fully understand all of the skin barrier elements that are
influential in the eczematous hand as this could have profound
therapeutic ramifications. Non-invasive bioengineering methods,
including the measurement of transepidermal water loss (TEWL)
and water capacitance, have been commonly used to evaluate skin
barrier function. Studies also suggest that ionic signals such as calcium and potassium play an important role in the homeostatic
mechanism of the epidermal barrier function. Delineating changes
in these skin barrier functions may offer not only more robust and
early signals of normalization, but may aid clearer separation of
the aetiological processes than morphology alone and allow differentiating factors in the various forms of HE to be pinpointed.
Only by serially documenting skin barrier function in CHE may
we 1 day hope to fully understand this complex condition.
A brief summary of these methods is provided below.
1 Transepidermal Water Loss In the 1960s Malten and
Spruit13 pioneered the technique of measuring water transport through the skin. Many publications have been
devoted to TEWL; however, other areas of barrier function
have consequently been neglected.
2 Molecules involved in regulating barrier functions:
Carbon dioxide14,15 The transport of CO2 has been
shown to vary in different types of HE
Chlorides16 Transepidermal chloride flux through
hydrated skin appears to be a viable method for determining stratum corneum function in vivo
Oxygen17
Potassium18 It has been found that damage to the epidermal water barrier does not necessarily result in damage
to the epidermal electrolyte barrier
Calcium is thought to play various roles in the formation
of the stratum corneum barrier and abnormal calcium
distribution is observed in psoriatic epidermis and also in
atopic eczema. Assessing its transepidermal movement in
different types of HE could therefore provide useful differentiating data.
3 Keratin metrics. The stratum corneum is removed via tapestripping and is measured both functionally and quantitatively.19 This method provides quantification of the sodium
hydroxide soluble protein fraction via a commercially available
protein assay. The amount of stratum corneum removed is of
relevance in establishing the concentration profile of chemicals
within this layer and hence the uptake of therapeutic drugs.
4 Messenger RNA (mRNA) in stripped skin when combined
with a ribonuclease protection assay allows the quantification of molecular changes.20 Studies have shown that multiple cytokine mRNA levels can be defined in these RNA
samples assessing not only the cytokine gene profiles, but
also potentially, the severity of common irritant vs. allergic
skin reactions. Measurements of cytokine mRNA may provide a method to distinguish irritant contact and allergic
contact dermatitis.
JEADV 2010, 24 (Suppl. 3), 120
Appropriately combining these simple, non-invasive, techniques

should allow us to gain new insights into the various morphologies that have been grouped together under the terminology of HE.
Unanswered questions
One enigma occurs in cases of hyperkeratotic psoriasiform
eczema. This presents as marginated hyperkeratosis on the hands
(with or without erythema) with psoriasiform hyperkeratosis of
the elbows and knees sometimes extending down the forearms.
Another variant has fissuring of the fingertips. However, histology
shows this condition to be spongiosis or eczema not psoriasis.
Many patients with severe psoriasiform or hyperkeratotic eczema
will only respond to occlusive therapy, although penetration data
suggests that it should not be required.21 Further investigations
with the currently available technologies may help to resolve these
issues.
Further areas of investigation

One area of investigation of barrier function is to compare how
the palm of the hand compares in reactivity with the dorsal hand
and the forearm when responding to irritants. Significant damage
can be performed to the palm and the dorsum of the hand with
very little change in morphology. Often, the morphology is so
hidden when the skin is irritated that a number of different tools
are needed to observe the damage that has been performed. One
extremely discriminating tool in very low grade irritancy dermatitis is squamometry where an adhesive disc is used as a harvesting
method for the superficial desquamating layer of the stratum corneum. The disc can then be rated by visual examination, weighting, optical measurement (with or without staining), image
analysis, protein assay or morphology.22 Novel approaches to
investigate the structure and barrier function of the skin include
atomic force microscopy of tape stripped skin and 5D intravital
tomography.23,24
Additional mechanistic and methodological details can be
found in Karan et al.25
Impact of CHE on society and the

patient
Dr J. English
In addition to the direct medical consequences of the disease,
CHE causes significant problems and burdens to patients and to
society.
Psychosocial burden of CHE

There is generally a social stigma associated with any visible skin
disease, which can be a significant burden for the patient. CHE is
localized on a highly visible area of the body the hands which
2010 The Authors

Table 1 Psychosocial consequences of hand eczema
more frequent in service work, production and medical nursing

careers, and the rate of change of occupation was as high as 18%
in some professions.
Type of disturbance
Percentage of
patients 199022
Percentage of
patients 200527
Handicap in leisure activities
50
72
Change in daily activities
32
56
Economic burden of CHE
Sleep disturbance
34
36
Mood disturbance
39
46
Avoided contact
33
Gave up hobbies
18
16
The impact of any disease on society is felt through economic loss,

both direct (from the cost to healthcare authorities of drug treatments or hospital physician visits) and indirect (absenteeism from
work because of illness).
The economic impact of HE is considerable. Direct medical
costs including treatment, medication and visits to the GP alone
have been estimated at 11 billion per year in the EU.2 These figures do not include direct non-medical costs such as travel, informal care, time and out-of-pocket costs, or the indirect nonmedical costs such as loss of productivity because of reduced performance at work or sick leave.28
A recent study examined the direct and indirect cost of illness
in work-related CHE in Germany using data from 151 patients
with occupational skin diseases.29 Information on resource utilization (e.g. drug use, rehabilitation, diagnostic tests, physician visits,
etc.) was recorded and unit costs for each type of resource utilization determined and multiplied. Indirect costs were calculated
according to the human-capital-method (days lost from work
multiplied by mean gross income estimated by the German Statutory Pension Fund for 2007). Analyses were performed for the
total group and by disease severity. The most frequent types of
costs identified were dermatologist visits, application of topical
corticosteroids and lost work days. Other resources used included
frequent PUVA therapy and inpatient rehabilitation. Indirect costs
were by far the largest proportion constituting 70% of the total
bill. Total annual costs of work-related CHE amounted to 8,799
per patient comparable with the costs incurred for severe psoriasis or atopic eczema.
As indirect costs are the critical cost drivers for CHE, a reduction in days lost from work and therefore the costs associated with
this absence, would provide the most potent reduction in costs to
society. An effective therapy should therefore provide a significant
cost saving to healthcare authorities and society in general.
are important organs of communication and expression. Any

impairment in function and form may result in major psychosocial problems such as anxiety, low self-esteem, and social phobia.
Severe CHE is associated with a significant lowering of quality of
life comparable with that of generalized eczema or psoriasis. A lack
of understanding of the disease in the general population contributes to the problem almost 50% of HE patients surveyed said
they suspected other people thought the disease was contagious
whilst 81% said that HE interferes with their daily life.26 The table
below shows some of the psychosocial consequences of CHE as
they were assessed in a population in 1990, and at a 15-year follow-up study in the same population (Table 1). The results
showed a variable and poor long-term prognosis in this population. The effects of these and other disturbances can be far reaching. Patients may avoid going on holiday because of the
difficulties of preparation and adaptation in a new location or
because of embarrassment exposing their body in swimwear. Hobbies may be abandoned because of allergic reactions to the tools
required.
Occupational burden of CHE

Chronic hand eczema has also been shown to be a major cause of
morbidity and lost earnings with symptoms such as itching, blisters and painful fissures limiting patients abilities to carry out
some occupations. A random sample of 20 000 people in
Gothenburg, Sweden, were sent a questionnaire asking about HE.
Eighty-three percentage of those contacted responded and, of
these people, 1238 had a confirmed diagnosis of HE.26 21.4% of
the HE sufferers reported at least one period of sick leave from
work lasting a minimum of 7 days, whilst 4.4% reported more
than five separate sick leave periods (of minimum 7 days duration).26 The mean total sick leave time during the previous year
was 4.0 weeks.
Other studies have shown similar results, although conducted
on a much shorter time scale. A postal survey of 758 Danish HE
patients showed that 57% of the 579 responders to this item in the
questionnaire reported sick leave because of occupational HE during the past 12 months. Of these, prolonged sick leave, defined as
more than 5 weeks per year, was reported by 19.9%.27
Hand eczema can also force patients to change occupation. The
Swedish study found that up to 8% of HE patients had been
forced to change jobs because of their disease.26 Changes were
JEADV 2010, 24 (Suppl. 3), 120
Impact of CHE on the patient

The impact of severe CHE on the individual patient cannot be
underestimated as its occupational, domestic, social and psychological impact is considerable. The occupational and psychosocial
impacts have been discussed in the previous section.
Domestic impact of CHE

Lack of sleep30 because of pain and itching adds to the cumulative
stresses of CHE, and together these can cause frustration amid
feelings that a patient is unable to cope with everyday life. This
can lead to a straining of interpersonal relationships. Adjustments
are also required in all aspects of home-life when patients begin to
experience the debilitating symptoms of CHE.
2010 The Authors

Benefits and limitations of current

treatment strategies
Photochemotherapy (PUVA): Photochemotherapy can be useful

in combination with other topical or systemic therapies but has a
considerable impact on a patients lifestyle and is not widely available.33 Of the controlled studies published, few have shown
evidence of more than limited efficacy in CHE, with no information available on the magnitude of response to treatment. Photochemotherapy, however, is an inconvenient treatment, requiring
numerous office or hospital visits.
Approximately 24% of patients with severe CHE are refractory
to topical treatment, and current treatment options for these
patients are clearly limited.2
Dr R. Graham-Brown
3. Systemic therapies
All of these factors, combined with a potentially increased fiscal

burden because of private medical bills and specialist products,
place an enormous strain on the CHE patient. Faced with a condition that can last for decades and physicians who are unable to
offer long-term solutions, burden of disease is a truly meaningful
concept.
Current and emerging treatment strategies in CHE
Chronic hand eczema is a disease with a multifactorial aetiology

and clinical presentation does not always correspond to disease
phenotype. Consequently, treatment objectives are universal, irrespective of phenotype, and include elimination or reduction of
exposure to causative factors, symptom control, and reduction of
frequency and severity of flares.
Patients with CHE require long-term management and therapy
is usually delivered in escalating steps.
1. Education and non-pharmacological methods

Initial treatment steps involve education regarding skin protection
measures and lifestyle changes to minimize exposure to allergens
or irritants. Hands may be protected with gloves to avoid exposure
to trigger factors, although the gloves themselves can sometimes
aggravate the condition. Emollient creams are standard therapy
for all patients and should be used irrespective of other treatments.
They prevent the skin from becoming dry, provide basic barrier
protection from irritants, help prevent itch and reduce the frequency of flare-ups.
2. Topical therapies
Topical corticosteroids: The initial medical intervention for CHE is
usually topical corticosteroids. They are fast acting and are effective in the short-term for controlling the disease in many patients;
however, their suitability is limited by rebound flare-ups, tachyphylaxis and lack of efficacy in severely affected patients.31 Longterm corticosteroid usage can also cause skin atrophy and may
contribute to further weakening of the skin barrier. This is particularly true for potent topical corticosteroids.
Topical immunomodulators: The topical immunomodulators
(pimecrolimus and tacrolimus) are not licensed for, but have been
investigated in, the treatment of mild to moderate CHE. A randomized, study in 294 patients with mild-to-moderate CHE compared a twice-daily application of pimecrolimus cream 1% (with
overnight occlusion) with a vehicle control.32 By the final visit on
day 22, there was only a trend (with no statistical significance),
towards greater clearance in patients who received pimecrolimus
than for those treated with vehicle cream.
JEADV 2010, 24 (Suppl. 3), 120
The off-licence use of systemic treatments has been reported, but

there is a lack of clinical evidence supporting their long-term efficacy and safety in this indication.
Oral corticosteroids: Whilst oral corticosteroids may be useful
for the immediate treatment of an acute flare, their long-term use
is generally not appropriate as they have significant side effects
and long-term toxicities.
Oral retinoids: Retinoids have been used successfully to treat different dermatological disorders since the early 1980s. While current retinoids have been proven to be effective for the treatment of
psoriasis, acne and some genodermatoses, there is little reported
evidence of the use of oral retinoids in CHE. A small exploratory
study of acitretin (40 mg daily) in patients with hyperkeratotic
eczema (n = 14 receiving active treatment) showed a decrease in
some symptoms of up to 50% at week 4 with no further improvement at week 8.34 However, it should be noted that the study did
not explicitly define the patient population in terms of either
severity or disease responsiveness.
Immunosuppressants: A study investigated the efficacy of ciclosporin (3 mg kg day) vs. betamethasone (0.05% cream) in 41
patients with CHE who had an inadequate response to topical corticosteroids.35 The total disease activity score decreased by 57% of
baseline in the ciclosporin group and 58% in the betamethasone
group. There was no difference in response between the treatments, and 50% of patients in both groups relapsed after treatment was stopped (during the 24-week relapse-observation
period).35 Ciclosporin is associated with kidney toxicity and
hypertension, and patients must be carefully monitored. Azathioprine has been shown to be effective in atopic eczema,36 and whilst
atopic eczema is a recognized risk factor for CHE, no specific studies in CHE have been performed.
A recent literature review of the current available treatment
options in CHE (developed as part of a long-term project to
improve standards of design and reporting in HE trials) examined
published trials from 1997 to 2003.37 This review described the
study designs and commented on the quality of reporting of the
trials. A total of 90 studies reported in 87 papers dealt with 11 different classes of interventions. Around 80% of the studies dealt
with just four interventions: ultraviolet light, topical corticosteroids,
2010 The Authors

radiation and systemic immunosuppressants. Of the 90 studies,

44 were case series, 15 were non-randomized controlled trials,
and the remaining 31 were randomized controlled trials (RCTs).
Of these 31 RCTs, 16 were parallel (one with cross-over design)
and 15 self-controlled. Only 11 of the RCTs adequately reported
eligibility criteria. The randomization method was described in
10, and there was adequate concealment of allocation in eight.
Masking the treatment allocation from both the study assessors
and patients was performed in 11 RCTs, and intention-to-treat
analysis was reported in four. Only 13 RCTs were 4 months or
longer in duration. No study reported a rationale for the sample
size, and in only one study had the outcome variable been validated. The authors concluded that the strength of the clinicaltrial evidence for the multitude of currently available options for
the treatment of CHE was limited, and not adequate to guide
clinical practice. Future trials in HE, they said, needed to be randomized, with a parallel group or self-controlled design, and use
validated and clinically relevant outcome measures.
Given the limitations of current treatments and the lack of consensus between prescribers, there is a clear, unmet need, for effective long-term management of severe CHE that is unresponsive to
potent topical corticosteroids.
Toctino (oral alitretinoin) a new

treatment for severe CHE: discovery,
pharmacology and pharmacokinetics
Dr J. Maares
Retinoids are vitamin A derivatives that can be either endogenous
physiological or synthetic and they display key regulatory functions in epidermal growth and differentiation. Treatment with retinoids is associated with specific class effects such as skin reactions
(mucocutaneous effects, dry skin, cheilitis), metabolic effects (elevations in triglycerides and cholesterol), and hepatic effects (elevations in transaminases and bilirubin).
Isotretinoin, etretinate, acitretin and alitretinoin all belong to
the class of retinoids. However, they differ from one another
because of their pharmacological properties.
Isotretinoin is a naturally occurring retinoid found in the body
in small quantities. It was approved for use in severe acne in 1982
and is still considered to be the most effective therapy available in
this indication.
Etretinate is a synthetic retinoid that was launched in 1986 and
was used primarily for the treatment of severe recalcitrant psoriasis
before being superseded by acitretin.
Alitretinoin (9-cis-retinoic acid) is an isomer of isotretinoin
(13-cis-retinoic acid). It is an endogenous physiological retinoid
and is the only drug that has been specifically developed for the
indication of CHE.
JEADV 2010, 24 (Suppl. 3), 120
There are two structurally distinct families of nuclear receptors

associated with the retinoids retinoic acid receptors (RARs) and
retinoid X receptors (RXRs).
Each of these families in turn contains three distinct receptors,
termed alpha, beta and gamma, with more isoforms belonging to
each subtype.38 The existence of numerous retinoid receptor isoforms may explain the complexity and pleiotropic activity of retinoids.39 RARs bind both all-trans- and 9-cis-retinoic acid, but only
9-cis-retinoic acid binds to RXRs.
Alitretinoin has been described as a panagonist of retinoid
receptors because it binds to RAR receptors and RXR receptors.
Binding to and activation of the various retinoid receptors might
be responsible for certain biological effects of alitretinoin, however,
no precise link has been shown between patterns of receptor binding and therapeutic activity in CHE. The exact mechanism of
action of alitretinoin in the treatment of CHE is currently
unknown.
Although structurally related to isotretinoin, alitretinoin is associated with significantly less suppression of human sebum secretion.40 This finding may account for the lack of efficacy
demonstrated by alitretinoin in a small acne trial, and suggests a
possible basis for the low incidence of mucocutaneous side effects
seen in the alitretinoin clinical development programme.40,41
Early dose-finding studies assessed single ascending and multiple oral doses in healthy volunteers and oncology patients of up to
150 mg m2.42,43 Pharmacokinetics were found to be linear over
the doses studied. Single-dose peak plasma concentrations were
achieved within 34 h on average, the half-life was 1.32.4 h and
the drug was eliminated within 24 h. The drug tolerability was
consistent with other retinoids as were the adverse events (AEs),
including headache and diarrhoea, which were dose limiting at the
highest doses. Data from 32 CHE patients who received alitretinoin 10 mg or 30 mg for 24 weeks showed that the pharmacokinetics of the drug were linear and there was no evidence of timedependent pharmacokinetics or accumulation of alitretinoin.44
Drugdrug interaction studies of alitretinoin with inhibitors or
substrates of CYP 3A4 were conducted. When co-administered
with ketoconazole, a strong inhibitor of CYP 3A4, alitretinoin
AUC increased by 40% and Cmax by 60%. However, alitretinoin
did not affect the pharmacokinetics of ketoconazole or ciclosporin
A. A slight reduction of simvastatin plasma levels (AUC decreased
by 16% and Cmax by 23%) was observed when co-administered
with alitretinoin, although simvastatin and ciclosporin A did not
affect the pharmacokinetics of alitretinoin.45
Significant increases (P < 0.001) in the mean Cmax and mean
AUC have been observed when alitretinoin is given with food,
with systemic exposure enhanced by a factor of four, and variability of exposure markedly decreased.46 Alitretinoin should therefore
always be taken with a meal. No influence of body weight on alitretinoin exposure was noted in pharmacology trials. Correspondingly, no correlation between body weight and clinical response
was noted in clinical trials.
2010 The Authors

Like all retinoids, alitretinoin is a strong teratogen and strict

pregnancy prevention measures must be observed before, during
and after treatment. Alitretinoin has a shorter half-life (mean t
210 h) than acitretin (mean t 3996 h). This is particularly relevant for females of childbearing potential as contraception is
required for 1-month post-treatment with alitretinoin compared
with 3 years for acitretin.
Alitretinoin has no clinically relevant pharmacokinetic interactions with the commonly prescribed combined oral contraceptive
(COC) ethinyl estradiol norgestimate, suggesting COCs are an
appropriate primary method of contraception. For male patients,
the amount of alitretinoin (or its metabolite) transferred by seminal fluid to female partners is negligible, and therefore barrier contraception is not required during treatment.
Hapten
Irritant
Lymph Node
Toctino (oral alitretinoin) explaining

the anti-inflammatory effect
Professor B. Homey
Chronic hand eczema has been shown to be caused by exposure
to either irritant or allergic atopic trigger factors. Although the
clinical features of CHE are well defined, the underlying pathophysiological mechanisms are still not fully understood. In contrast to direct tissue damage induced by chemical irritants or
mechanical injury, which subsequently leads to local inflammation, the induction of allergic responses by haptens or allergens
activates not only the epidermal compartment but also the
immune system, characterized by the induction of antigen-specific
effector and memory T cells. The recruitment of distinct leucocyte
subsets to sites of inflammation has been shown to be critically
regulated by chemokines and their receptors.
During contact irritancy, structural cells as well as resident cells
of the skin immune system are primarily activated, and primary
pro-inflammatory cytokines such as TNF-a and IL-1 family members are induced, and will in turn mediate the recruitment of distant subsets of the immune system to the skin which will induce
contact irritancy. During an allergic reaction, haptens and allergens
activate not only the resident structural cells but also resident antigen-presenting cells which, in turn, migrate to local draining
lymph nodes and present the allergen to specific T-cells. These
cells differentiate into allergen-specific memory T-cells, re-circulate
and on subsequent contact with the specific allergen, they extravasate, get in contact with antigen-presenting cells, which present the
specific allergen to the effector memory T cells. These effector
memory T cells will then produce effector cytokines. In CHE we
find a predominance of the production of Type 1 effector cytokines, which are represented by interferon-c. An excess of IL-4
production is also found in CHE lesions (Fig. 1).
There are bi-directional communication pathways between
structural cells of the skin and the immune system, and the traf-
JEADV 2010, 24 (Suppl. 3), 120
Figure 1 Skin immune system.
ficking of leucocytes within the system is of major importance. A

family of small, cytokine-like proteins called chemokines play a
crucial role in directing the migration of leucocyte subsets to the
skin. Within the multistep process of leucocyte extravasation, the
chemokines which are expressed at the membrane of the endothelial cells will mediate the adhesion of the leucocytes to the
endothelium, and are the stimulus for the leucocytes to perform
trans-endothelial migration from the blood vessel to perivascular
pockets. Subsequently, matrix-bound chemokine gradients will
further direct distinct leucocyte subsets from perivascular pockets
to sub-epidermal or intra-epidermal locations.
These situations can be reproduced in the laboratory in mice
models where distinct molecular signatures differentiating irritancy
and allergy can be elucidated.47 Independent of overall skin
inflammation, it has been found that a particular set of interferonc inducible chemokines, CXCL9 and CXCL10 are elevated only in
allergic contact eczema, but not in the irritant form. In contact irritancy primary pro-inflammatory cytokines TNF-a and IL-1 family members play a major role, and a non-allergy specific
chemokine CCL20 is elevated.
Alitretinoin may interfere at different steps in the inflammation
process seen in chronic contact eczema: (i) at the level of chemokine production, (ii) at the level of leucocyte activation and (iii) at
the level of antigen allergen presentation.
Recent data have shown that within structural cells, alitretinoin
markedly suppresses the expression of chemokines thought to be
pathogenically relevant, suggesting that the drug may impair the
recruitment of the distinct leucocyte subsets to sites of skin inflammation. Via this mechanism, alitretinoin may interfere with the
initiation as well as the maintenance of contact eczema lesions.
In contrast to isotretinoin, alitretinoin also markedly impairs
mixed leucocyte reactions. Detailed flow cytometric analyses
have shown significant dose-dependent suppression of activation-
2010 The Authors

Figure 2 Effects of alitretinoin.
associated molecules on the surface of activated T cells by alitretinoin. Alitretinoin has also been shown to suppress leucocyte activation in a dose-dependent manner.
The interaction of the antigen-presenting cell with the memory
T cell is crucial for the differentiation and activation of the latter,
and for the amplification of the immune response within the skin.
For the effective activation of the lymphocyte, the dendritic cell
has to provide co-stimulatory molecules. Without those the lymphocyte becomes tolerant and will not be activated. Alitretinoin
has been shown to significantly suppress the expression of these
co-stimulatory molecules on the surface of the antigen-presenting
cells.
In conclusion alitretinoin may interfere at different steps in the
inflammation process seen in chronic contact dermatitis (Fig. 2):
1 At early phases, alitretinoin may interfere with cytokineinduced chemokine production in structural cells of the
skin and interfere with the recruitment of pathogenic leucocyte subsets to the skin.
2 In leucocytes, alitretinoin may modulate activation processes and interfere with the upregulation of the co-stimulatory molecules. In turn, effective antigen presentation might
be altered, leading towards impaired leucocyte activation,
proliferation and expansion.
These first insights into the mechanisms of action of alitretinoin
may help in the understanding of its clinical efficacy and provide
perspectives for future indications.

treatment for severe CHE: efficacy in
pivotal clinical trial
Dr C. Lynde
Results
Alitretinoin is currently the only evidence-based therapy option

for patients with severe CHE unresponsive to potent topical corticosteroids.
JEADV 2010, 24 (Suppl. 3), 120
Alitretinoin has been studied in a large randomized, multicentre, placebo-controlled, double-blind study in 111 dermatology
clinics in Europe and Canada. The BACH study (Benefit of Alitretinoin in Chronic Hand Eczema), is the largest controlled trial in
CHE to date.48 A total of 1032 patients with severe CHE unresponsive to topical corticosteroids were randomized in a 2 : 2 : 1
ratio to alitretinoin 10 mg (n = 418), 30 mg (n = 409) or placebo
(n = 205). The drug was administered orally once daily for up to
24 weeks to determine whether alitretinoin was superior to placebo in reducing the signs and symptoms of CHE.48 Throughout
the study, patients were provided with a standardized emollient to
apply several times a day. No concomitant topical or systemic
medicated treatment for CHE was allowed during treatment or
during the relapse-observation period. The primary endpoint was
the percentage of patients with a physicians global assessment
(PGA) rating of clear or almost clear hands (defined as
response). Secondary endpoints included patients global assessment (PaGA), Modified Total Lesion Symptom Score (mTLSS),
extent of disease, time to response and time to relapse. Safety was
assessed for all patients during a follow-up period of 4 weeks, and
responders were observed for relapse for 24 weeks after the end of
therapy. Patients with psoriatic lesions were excluded from the
study as were patients with atopic eczema whose condition
required a medicated treatment.
The PGA attempts to offer an objective assessment of disease
severity. Using a pre-defined guide, physicians rate patients severity of CHE according to a 5-point scale from clear to severe
(Table 9). A validated photographic guide is used to support consistent and reproducible grading of overall CHE severity for the
PGA (Fig. 12).
The mTLSS is a composite measure of the intensity of seven
individual CHE signs and symptoms erythema, oedema, desquamation, fissures, hyperkeratosis lichenification, pruritus pain and,
vesicles. Each sign or symptom is rated by the physician on a 4point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe), with
the mTLSS calculated as the sum of assigned individual scores
with a maximum value of 21 (most severe disease) and a minimum of 0 (no disease) (Table 10).
Male patients or female patients (either post-menopausal or
prepared to enter a pregnancy prevention programme) aged 18
75 years were enrolled. Patients were eligible for inclusion providing their disease was persisting for at least 6 months since initial
diagnosis, was rated severe according to the PGA and was unresponsive to avoidance of irritants and allergens, non-medicated
treatments and standard therapy including potent topical corticosteroids. All types of CHE were eligible for inclusion including
hyperkeratotic, vesicular (e.g. pompholyx) and fingertip.
The patient groups were well matched with regard to demographics and disease characteristics (Table 2). The majority of patients
had hyperkeratotic CHE, however, phenotypes were not mutually
2010 The Authors

Table 2 Patient demographics

Alitretinoin
Patients in ITT population (n)
Placebo
205
10 mg
30 mg
418
409
Mean age (years)
47.9
47.3
48.5
Sex (% male)
59
56.9
54.5
Females <45 years (%)
15.1
15.1
14.7
Race (% Caucasian)
99
96.2
97.3
Types of hand eczema (%)

Hyperkeratotic
82.9
86.6
85.3
Pompholyx
26.8
26.6
27.1
Fingertip
49.3
43.1
47.9
Other
14.1
14.5
13.4
Duration of disease (mean years SD)
9.1 10.0
8.7 10.2
9.3 10.3
Response to potent topical corticosteroids (%)

No response
39.5
43.3
48.2
Transient response
59
53.1
48.7
1.2
2.9
Not tolerated
exclusive and the majority of patients with hyperkeratosis also had

signs of inflammation such as erythema and vesicles. The average
age of patients enrolled in the trial was relatively high. A lower
proportion of younger women than would be expected in the general patient population were enrolled, as alitretinoin, like other retinoids, is highly teratogenic and therefore requires the
implementation of a strict pregnancy prevention programme
amongst women of child-bearing potential.
Response rates for achieving clear or almost clear hands were
markedly higher in the alitretinoin 30 mg (48%; 195 of 409
patients) and 10 mg (28%; 115 of 418) groups compared with placebo (17%; 34 of 205) (Fig. 3). Complete clearance was achieved
in a higher proportion in the alitretinoin 30 mg (n = 90) and
10 mg (n = 39) groups compared with placebo (n = 6). Placebo
response rates were comparable with those seen in other dermatol-
ogy studies. Inclusion in the placebo group entailed intense overall

management including use of emollients and clinical consultations, which are both likely to have been more rigorous and frequent than patients normal routine.
The study was not powered to detect differences in efficacy
between differing classifications of CHE, but it appears that the
activity of alitretinoin was not limited to patients with any distinct
combination of eczema signs and symptoms (Table 3). Response
rates were highest for the 85% of patients who were classified as
having hyperkeratotic CHE at baseline. However, CHE types were
not mutually exclusive, as nearly all (99%) of CHE patients classified as predominantly hyperkeratotic by the investigator had also
signs of inflammation, such as erythema and vesiculation.
The time to response was significantly shorter in the alitretinoin
30 mg group compared with alitretinoin 10 mg or placebo
(P < 0.001). Figure 4 depicts the cumulative response for the three
treatment arms over the study period. By week 12, there was a
clear separation in response between all the three groups (4% in
placebo vs. 11% in 10 mg vs. 28% in 30 mg). The median time to
response (clear or almost clear hands) for patients responding
to treatment with alitretinoin 30 mg was 12.1 weeks, which is an
Table 3 Responders by disease subtype

Alitretinoin
30 mg
10 mg
170 349 (49)
102 362 (28)
Placebo
21 170 (12)
Pompholyx
responders, n (%)
37 111 (33)
25 111 (23)
9 55 (16)
Fingertip
responders, n (%)
87 196 (44)
53 180 (29)
18 101 (18)
Classification
Hyperkeratotic
responders, n (%)
Figure 3 Patients with clear or almost clear hands at the end

of treatment.
JEADV 2010, 24 (Suppl. 3), 120
2010 The Authors

10
Figure 4 Time to response [Intent-To-Treat (ITT) population].

Figure 6 Improvement in signs and symptoms over time: median % reduction in mTLSS (ITT population).
tretinoin 30 mg compared with placebo (75% vs. 33%;

P < 0.001).
Conclusions
Figure 5 Correlation between physicians global assessment

and patients global assessment scores.
encouraging result for patients whose condition could not be sufficiently managed over many years.
There was a good correlation between the primary efficacy
parameter (PGA) and the PaGA (correlation coefficient 0.82; Kendalls tau) (Fig. 5). This consistency may reflect the use of a categorical scale of severity instead of an estimated degree of
improvement, and lack of ambiguity in the definition of response,
corresponding to complete or nearly complete resolution of previously severe disease.
Alitretinoin 30 mg produced a median change from baseline in
mTLSS of 58% at week 12 and 75% by week 24 (Fig. 6).
Improvements were seen in all seven of the individual signs and
symptoms that make up the mTLSS, and none showed plateaux at
the end of the study, suggesting extension treatment beyond
24 weeks may lead to further responses of clear or almost clear
hands (Fig. 7).
Extent of disease was evaluated and was defined as the percentage of hand area (with 100% defined as the palmar and dorsal aspects) affected by disease. The median reduction in extent
of disease was significantly reduced following treatment with ali-
JEADV 2010, 24 (Suppl. 3), 120
The results from the BACH study show that oral alitretinoin is
highly effective in treating severe CHE unresponsive to potent topical corticosteroids. A 75% reduction in signs and symptoms of
CHE after 24 weeks was observed following alitretinoin treatment
with 48% of patients having clear or almost clear skin within
1224 weeks. All individual symptoms of CHE improved and alitretinoin was efficacious in all forms of CHE, with highest
response in hyperkeratotic disease.
With alitretinoin, patients and physicians will have, for the first
time, a convenient, safe and effective oral treatment licensed for
severe cases of CHE, when topical corticosteroids have not led to
improvement, and patient quality of life is severely affected.

treatment for severe CHE:
retreating patients with CHE
Professor P. Elsner
In the BACH study, alitretinoin demonstrated high efficacy in the
treatment of severe CHE in patients who were unresponsive to
treatment with potent topical corticosteroids.48
Patients who had responded by the end of the BACH trial were
followed up for relapse during a 24-week observation period.
Relapse was defined as an mTLSS score 75% that of their baseline
score in the BACH trial. Only one-third of the BACH responders
relapsed within the 24-week follow-up period (116 344 responders; 33.7%).
At the end of the follow-up 24-week observation period, two
categories of patients were eligible to take part in a retreatment
study, designed to evaluate the efficacy and safety of a second 12to 24-week course of oral alitretinoin:49 (i) patients who did ini-
2010 The Authors

11
Figure 7 Individual components of the mTLSS in patients responding with clear or almost clear hands in the alitretinoin 30 mg
group.
tially respond but relapsed within 24 weeks after completion of

treatment (cohort A); (ii) patients who did not respond and were
rated mild or moderate according to the PGA at end of the BACH
study (cohort B).
Results from cohort A

One hundred and seventeen patients were included in a doubleblind, randomized, placebo-controlled, multicentre study and were
randomized to receive their previous treatment (either alitretinoin
10 mg or 30 mg daily) or placebo, for up to 24 weeks.
JEADV 2010, 24 (Suppl. 3), 120
Baseline patient characteristics are presented in Table 4. Subjects

were predominantly Caucasian with a mean age of between 49
and 52 years. The majority of patients had hyperkeratotic CHE,
but categories were not mutually exclusive.
The primary efficacy parameter was the PGA and response was
defined as clear or almost clear hands at the end of treatment.
Response rates were 79.6% (n = 39) in patients retreated with alitretinoin 30 mg compared with 8.3% (n = 2) for placebo
(P < 0.001) (Fig. 8). In patients retreated with alitretinoin 10 mg
response rates were 47.6% (n = 10) compared with 10.0% (n = 1)
2010 The Authors

12
Table 4 Baseline patient characteristics (cohort A)

Placebo
Table 5 Baseline patient characteristics (cohort B)
Alitretinoin
10 mg
Alitretinoin
30 mg
Alitretinoin
30 mg
47
21
49
Mean age (years)
50.4
49
52
Mean age (years)
46.3
Sex (% male)
51.1
71.4
51
Male (%)
58.8
14.4
Caucasian (%)
98.4
98
Physicians global assessment at baseline (%)
Females <45 years (%)

Caucasian (%)
8.5
100
4.8
95.2
Clear
Physicians global assessment at baseline (%)
243
Clear
Almost clear
Almost clear
4.8
Mild
21.8
Moderate
56.0
Severe
21.8
Mild disease
4.8
Moderate disease
38.3
42.9
30.6
Severe disease
61.7
47.6
69.4
Duration of current chronic hand eczema (mean months)
0.4
34.3
Type of hand eczema (%)
Types of hand eczema (%)

Hyperkeratotic
72.3
85.7
91.8
Hyperkeratotic
81.5
Pompholyx
19.1
19
18.4
Pompholyx
26.3
Fingertip
31.9
23.8
30.6
Fingertip
37.0
Other
34
14.3
10.2
Other
15.6
90.0% for patients in the 30 mg group and 46.7% for patients

who received alitretinoin 10 mg.
Results from cohort B
Figure 8 Response rate at end of treatment in patients who

relapsed after initial treatment of severe chronic hand eczema
(physicians global assessment) (cohort A).
in the placebo group. Of the responders in the alitretinoin 30 mg

arm, 42.9% (n = 21) had a PGA rating of clear and 21 patients
responded by week 12. Of the responders in the alitretinoin 10 mg
arm, 20% (n = 2) had a PGA rating of clear and three patients
responded by week 12. Amongst the 13 patients in this trial who
had responded to placebo in the initial BACH study, nine patients
(69.2%) responded to placebo again.
Secondary endpoints were consistent with PGA results. The
median percentage reduction in mTLSS scores was 92.3% for
patients receiving alitretinoin 30 mg and 70.8% for patients receiving 10 mg. PaGA results were consistent with those observed for
the PGA with 75.5% of patients treated with alitretinoin 30 mg
and 38.1% in the 10 mg group reporting clear or almost clear
hands. Median percentage reduction in the extent of disease was
JEADV 2010, 24 (Suppl. 3), 120
Patients who did not respond with clear almost clear hands in the
BACH study, and who were presenting with mild or moderate
CHE at the end of the study were eligible to receive a second
course of alitretinoin treatment (cohort B). These patients were
included in an open-label, multicentre study design and received
30 mg of alitretinoin independent of their previous treatment in
the BACH trial for up to 24 weeks. Patient demographics for
cohort B are presented in Table 5.
Overall, approximately half of the patients, who did not
respond to an initial course of treatment, responded to
Figure 9 Response to retreatment with alitretinoin 30 mg in

patients who had previously not responded to treatment (cohort
B).
2010 The Authors

retreatment with alitretinoin 30 mg. The response rates in cohort

B by previous treatment in the BACH trial were 50.4% for alitretinoin 10 mg, 39.1% for 30 mg and 50.9% for placebo (Fig. 9).
Results for cohort B suggest that either a higher dose or a longer
treatment period may benefit patients who have initially failed to
respond to alitretinoin treatment.
13

treatment for severe CHE: safety in
clinical trials
[Study C] A double-blind, placebo-controlled, randomized

study that included patients who responded to initial treatment in
the BACH study and relapsed within 24 weeks. One hundred and
seventeen patients were re-randomized to a second course of the
same dose of alitretinoin or placebo for up to 24 weeks.
Alitretinoin was well tolerated in the treatment of patients with
severe CHE unresponsive to treatment with topical corticosteroids.
Special safety assessments were performed in the BACH study
(study A) and in the re-treatment study (study C). No differences
in psychiatric questionnaires (Centre for Epidemiological Studies
Depression Scale, General Health Questionnaire) or in the incidence or severity of psychiatric AEs were observed between the
treatment groups. Similarly, bone density assessments or skeletal
radiographs did not reveal any effect of dosing on bone mineralization or extraosseous calcifications. Beside dry eyes no other
treatment related effects were observed in ophthalmological assessments. In addition, electroretinograms were performed in a pharmacology study involving 32 patients exposed for 24 weeks. No
effect on retinal function was observed. In the clinical programme,
two fatalities occurred in patients receiving the 10 mg dose. Both
events (myocardial infarction and acute cardiac failure) were
assessed as unrelated to the treatment.
Dr R. Bissonnette
Adverse events
The efficacy of alitretinoin in the treatment of severe CHE has

been studied via safety and tolerability assessments performed
throughout the clinical development programme. This section will
review only the large phase III clinical trial data, however, safety
results from earlier phase II trials are consistent with the data presented here.
Three trials are discussed in this section:
Patients in all three studies had severe CHE unresponsive to
potent topical corticosteroids.
[Study A] The BACH study conducted in 111 centres in Europe
and Canada a double-blind, randomized, placebo-controlled,
parallel-group trial in 1032 patients who received alitretinoin
10 mg (n = 418) or 30 mg (n = 409), or placebo (n = 205) oncedaily for 12 or 24 weeks depending on response to treatment.
Patients were provided with a standardized emollient to apply several times a day. No concomitant topical or systemic medication
for CHE was allowed during treatment or during the relapseobservation period. Alitretinoin intake could be interrupted for
tolerability reasons, but dose reductions were not allowed.48
[Study B] An open-label, non-comparative, single fixed-dose
study in 249 patients from 37 centres in Europe and Canada.
Patients received oral, once-daily treatment with alitretinoin
30 mg for up to 24 weeks. As in the previous BACH study, dose
interruptions were allowed if necessary to manage AEs. Unlike the
previous study, dose reductions were allowed to emulate the dose
adjustments for the management of tolerability that are likely to
occur in clinical practice with oral retinoids.50
Adverse events (AEs) were generally dose-dependent, manageable

and consistent with other compounds in the retinoid class. Headache was the most commonly occurring AE in patients treated
with alitretinoin 30 mg, and the most common reason for study
withdrawal (Table 6).
[Study A] Headache was reported as an AE in 6.4%, 10.8% and
19.8% of patients taking placebo, alitretinoin 10 mg or alitretinoin
30 mg respectively. Headache led to 17 (4.1%) patient withdrawals
in the 30 mg group, six (1.4%) in the 10 mg group, and one
(0.5%) in the placebo group. No other AE caused more than two
withdrawals in any group. There were seven cases (1.7%) of headache rated as severe with alitretinoin 10 mg, compared with 19
(4.6%) with 30 mg, and none with placebo.
[Study B] A total of 18.5% of patients reported headache as an
AE. Out of 21 (8.5%) of patients who withdrew because of AEs,
nine (3.6%) were because of headache. Severe headache was
reported in 6% of alitretinoin 30 mg patients. In 29 cases, headache was managed using analgesics alone (paracetamol or ibuprofen). Headache led to dose reduction to 10 mg in 15 patients (six
were subsequently increased to 20 mg or 30 mg); two patients
interrupted treatment because of headache. Time of onset of
headache showed no specific pattern; two cases occurred prior to
first exposure to drug, 34 cases within 10 days of treatment initiation and 28 cases within 3 days of treatment initiation. Of the
three serious AEs occurring in the open-label study, only one was
considered to be remotely treatment related a case of angioneurotic oedema that resolved following discontinuation of treatment. The pathophysiology of these headaches (as with other
Conclusion
The majority of patients with CHE who had previously responded
to alitretinoin treatment, i.e. who had achieved clear or almost
clear hands and had relapsed within 6 months, responded to a
second course of treatment.
Patients who had not responded to an initial course of alitretinoin treatment, be it 10 mg or 30 mg, in the 24 week study period,
did achieve clear or almost clear hands in half of the cases following an additional treatment course of alitretinoin 30 mg for up
to 24 weeks.
JEADV 2010, 24 (Suppl. 3), 120
2010 The Authors

14
Table 6 Common adverse events reported in at least 3% of patients in any treatment group
Study A
Study B
Study C
Treatment emergent AEs 3%

in any group
Placebo
(n = 203)
Alitretinoin
10 mg
(n = 418)
Alitretinoin
30 mg
(n = 410)
Alitretinoin
30 mg
(n = 248)
Placebo
(n = 46)
Alitretinoin
10 mg
(n = 21)
Alitretinoin
30 mg
(n = 50)
Patients with any AEs
49.8
51.7
59.5
54.4
26.1
42.9
44
Nasopharyngitis
6.9
5.3
5.9
9.3
4.3
4.8
Upper RTI
1.2
2.2
1.2
Erythema
1.5
1.7
7.3
4.8
Eczema
4.9
3.8
3.2
1.2
2.2
12
Dermatitis
2.5
1.7
1.7
0.8
2.2
4.8
Pruritus
0.7
0.7
3.2
Headache
6.4
10.8
19.8
18.5
14
Dry lips
2.2
3.7
1.2
2.2
Nausea
1.5
2.4
3.4
2.4
Dry mouth
2.4
2.4
1.6
2.2
4.8
Flushing
1.2
4.4
6.9
Blood CPK elevated
1.9
3.2
2.4
Blood triglyceride elevated
0.7
2.9
0.8
4.8
AE, adverse event; CPK, creatinine phosphokinase.
retinoids) is unknown. The headaches were described predominantly as tension-type headaches and tended to occur early in
treatment.
[Study C] Headache was the most frequently occurring AE and
all reports of headache occurred in the 30 mg group (14.0%). A
single patient (2.0%) from the 30 mg group withdrew because of
headache. There were two (4.0%) cases of headache rated as severe
by the investigator in the alitretinoin 30 mg group. No severe
headaches were reported in either the placebo or alitretinoin
10 mg groups.
Overall, in the three studies, mucocutaneous effects (any of the
following: dry lips, cheilitis, dry skin, dry mouth, dry eyes)
occurred in approximately 10% of patients. This is a lower incidence than that reported for other retinoids.
noids, there was little or no apparent effect on hepatic enzyme or

bilirubin levels.
[Study B] The profile of laboratory abnormalities in Study B
was similar to that of the alitretinoin 30 mg group in study A.
[Study C] In the retreatment study, where patients who initially
responded to alitretinoin but later relapsed were exposed to a second 1224 week course of drug, alitretinoin remained well tolerated. No significant late-arising toxicities were observed (255
patients received alitretinoin treatment for a maximum period of
48 weeks).
Table 7 Marked laboratory abnormalities in study A
Laboratory parameter
Placebo
Alitretinoin Alitretinoin
10 mg
30 mg
TSH high
Marked laboratory abnormalities
>7.4 mU L (age 20 years)
[Study A] Observed laboratory abnormalities were typical effects

of retinoids. Increases in serum cholesterol and triglyceride levels
were the most commonly reported marked abnormalities
(Table 7). These changes either resolved or improved markedly
within 4 weeks after the end of therapy. Three cases of hypercholesterolemia were either present at baseline or were non-fasting
values. About half of the patients with marked abnormal increases
in serum cholesterol or triglyceride levels in this retreatment study
had similar abnormalities during the initial BACH trial. Reduced
thyroid-stimulating hormone (TSH) levels were reported in the
alitretinoin 30 mg group (Table 7). Reductions in TSH levels were
not always accompanied by corresponding reductions in T4. No
clinical hypothyroidism was observed and no patient required any
clinical intervention during the study (such as dose interruption,
supplementation with thyroid hormones, etc.). Unlike other reti-
>6.3 mU L (age >20 years)
JEADV 2010, 24 (Suppl. 3), 120
1 50 (2.0)
4 50 (8.0)
2 50 (4.0)
TSH low
<0.6 mU L (age 20 years)
<0.3 mU L (age >20 years)
Thyroxine low
<8.3 pmol L (age 65 years)
<8.0 pmol L (age >65 years)
Cholesterol high
(>7.77 mmol L)
1 33 (3.0) 2 17 (11.8)
8 38 (21.1)
Triglycerides high
(>5.66 mmol L)
1 33 (3.0)
5 38 (13.2)
1 17 (5.9)
AST high
>90 U L (Male)
2 50 (4.0)
1 50 (2.0)
>72 U L (Female)
Bilirubin high (>37 lmol L)
Values in parentheses are in percentages.
2010 The Authors

Conclusions
Throughout the clinical development programme, alitretinoin has
been subjected to rigorous safety assessments. Alitretinoin is well
tolerated in the treatment of patients with severe CHE unresponsive to topical corticosteroids at doses up to 30 mg. AEs are
dose-dependent, manageable and consistent with retinoid class
effects headache being the most commonly occurring AE. As
expected, the incidence of mucocutaneous effects seen in these
trials is lower than that reported for other retinoids including isotretinoin, occurring in less than 10% of patients receiving the
30 mg dose. No relationship between alitretinoin treatment and
any psychiatric disorders were seen and there were no reports of
sticky skin, desquamation, hair loss or photosensitivity. No significant late-arising toxicities were observed in patients receiving a
second treatment cycle or whose treatment was continued for a
further 1224 weeks. These findings suggest that a second course
of alitretinoin is well tolerated.
Advancing CHE management in

clinical practice
CHE treatment guidelines and their
role in good clinical practice
15
based system. The Cochrane Collaboration is an international

organization formed in 1993 that aims to help people make well
informed decisions about healthcare by preparing, maintaining
and promoting the accessibility of systematic reviews of the effects
of healthcare interventions. The Cochrane Skin Group (formed in
1996) is part of this collaboration. Systematic reviews are characterized by, clear and focused study questions, explicit definition of
study criteria and a priori protocol for collating evidence. They are
an exhaustive search of the available literature (including handsearching and unpublished studies) provide explicit or implicit
factoring of study quality and are the most comprehensive
resource for therapy questions.
Guidelines
The interplay of factors involved in clinical decision-making are
summarized below (Fig. 10). Guidelines are helpful in aiding the
physician in the evaluation of all of these factors and in allowing
them to make more informed clinical decisions. They also give
weight to physicians recommendations and can help to influence
policy makers and reimbursement agencies whilst diffusing potential litigations. Guidelines are also useful in delivering novel treatments to patients far faster than a system of filtration from
opinion leaders, through the medical hierarchy.
German guidelines
Professor T. L. Diepgen
Given the lack of an accepted classification for HE, the use of
EBM can provide a more comprehensive method of classification that allows the different mechanisms, morphological forms
and manifestations of HE to be systematically catalogued and
evaluated within the framework of the currently available treatment options.
Guidelines for the management of HE have recently been developed in Germany in association with the German Dermatology
Association (DDG).51 These guidelines recommend the use of alitretinoin for persistent or chronic relapsing HE when class 24
topical glucocorticoids and or UV therapy have failed.
Classification
There is no simple definition of HE. A comprehensive classification should take into account the different causative mechanisms
Evidence-based medicine
Often clinical experience does not give sufficient evidence to
guide clinical practice it is a very valid source of information but
it is not systematic and is often not supported by rigorous clinical
trial data. Expert opinions can dominate in the absence of evidence, and non-systematic reviews can be biased. The abundance
of medical literature can make it difficult for any individual physician to be fully up-to-date with all of the current work within a
field and this is where EBM can provide valuable support.
The conscientious, explicit, and judicious use of current best
evidence in making clinical decisions about the care of individual
patients was how Dr David Sackett, the father of EBM, described
this area of medicine. EBM is not cookbook medicine, it is a process by which evidence is integrated with patient preferences and
provider expertise (including knowledge of what makes a patient
unique). Systematic reviews play a crucial part in this evidence-
JEADV 2010, 24 (Suppl. 3), 120
Figure 10 Factors that enter into clinical decisions.
2010 The Authors

16
Table 8 Classification of hand eczema: overlapping disease

entities, multifactorial aetiologies and mixed forms are common
Aetiology (types of HE)
Irritant (subtoxic cumulative HE)
Allergic HE
(exogenous vs. endogenous), various morphological forms (such

as vesicular [dyshidrotic], hyperkeratotic rhagadiform and nummular), and different sites of HE manifestation (such as dorsal,
palmar and interdigital HE). These are summarized below
(Table 8).
Atopic HE
Protein contact dermatitis
Recommendations
Other (genuine pompholyx type, tylotic HE, etc.)
The recommendations from the German guidelines are summarized below.
Site
Dorsum
Palm
Sides of the fingers
Fingertips
Finger webs
Wrists
1. History taking
Occupational
Exposure profile
Known allergies
Morphology
Dyshidrotic (vesicular)
Erythema, desquamation
Hyperkeratotic rhagadiform (=tylotic)
Nummular
2. Diagnostic procedures
Allergen tests (patch testing, skin prick testing)

Histological examination where appropriate
Rule out possible fungal infections
HE, hand eczema.
+ systemic
immunomodulatory
therapy (eg alitretinoin
or ciclosporin A)
Step 4: Persistent or chronic

relapsing HE
+ Class 24
topical
glucocorticoids
+ antipruritic and antiseptic
drugs, Class 2 topical
glucocorticoids and/or topical
calcineurin inhibitors
Topical background therapy: skin hydration,
emollients,
avoidance or reduction of triggers
Step 3: Moderate HE
Step 2: Mild HE
Step 1: Dry skin
Figure 11 Therapeutic options.
JEADV 2010, 24 (Suppl. 3), 120
2010 The Authors

17
Table 9 Physicians global assessment (PGA)43

PGA severity
Features
Intensity
Area involved
Severe
Erythema, scaling, hyperkeratosis lichenification
At least one moderate or severe
>30% of affected hand surface
Vesiculation, oedema, fissures, pruritus pain
At least one severe
Moderate
Mild
Almost clear
Clear
At least one mild or moderate
At least one moderate
At least one mild
At least one mild
1030% of affected hand surface

Less than 10% of affected
hand surface
At least one mild
Absent
Less than 10% of affected

hand surface
Absent
Not detectable
Absent
Figure 12 Photographic severity guide used in physicians global assessment scoring.10
3. Preventative measures
Primary prevention education regarding behavioural prevention strategies, control of individual risk factors, and
environmental prevention strategies
Secondary prevention dermatologist procedures to spot
skin changes early on, to enable early institution of preventative measures
Tertiary prevention concerted (in outpatient) and interdisciplinary (occupational dermatology, industrial health,
health educational, occupational therapeutic, psychological, and trade association-administrative) interventions
4. Therapy (see Fig. 11)
Using Toctino (oral alitretinoin) in

day-to-day clinical practice answers
to some commonly asked questions
Oral treatment with alitretinoin treatment is started at a
dose of 30 mg. The dose can be reduced for the
JEADV 2010, 24 (Suppl. 3), 120
management of adverse reactions. Up-titration is an

option for patients whose dose was reduced or who were
started on a lower dose, e.g. for pre-existing cardiovascular conditions.
The absorption of alitretinoin is greatly affected by food.
Alitretinoin therefore should always be taken with a meal.
There is no need for dose adjustment according to body
weight as there is no correlation between body weight and
drug exposure or clinical response.
Clinical studies did not indicate a relationship between
psychiatric disorders and alitretinoin medication.
No photosensitivity has been observed following alitretinoin treatment.
As in the case of other retinoids, serum cholesterol and triglycerides should be monitored. The laboratory test interval may be
adapted to the response of the patients laboratory values to the
medication. Patients with cardiovascular risk factors require closer
monitoring, and if the risk pre-dates treatment initiation, an initial
dose of 10 mg is recommended.
2010 The Authors

18
Conclusions
Table 10 Modified total lesion symptom score
Severe CHE is a distressing illness that often runs a long-lasting,

relapsing course that causes significant burdens for both patients
and society. Current treatment strategies are extremely limited and
there is a clear and unmet medical need for an effective intermittent therapy to treat this chronic condition.
Alitretinoin is an endogenously occurring physiological vitamin
A derivative, and is at present the only product licensed for severe
CHE unresponsive to potent topical corticosteroids. The largest
study in CHE to date (BACH) showed that alitretinoin is highly
effective in clearing severe CHE. Alitretinoin has been shown to be
notably effective in the long-term management of CHE and is well
tolerated with a good safety profile. Given the chronic nature of
the disease, management of long-term effects is paramount, and
alitretinoin provides a breakthrough in this area because of its evidence-based long-term efficacy combined with good tolerability.
Like other retinoids, alitretinoin is a strong teratogen. Strict adherence to pregnancy prevention measures including pregnancy testing, contraceptive counselling and effective contraception are
required before, during and 1 month after cessation of treatment
for women of childbearing potential.
Alitretinoin offers patients with CHE unresponsive to potent
topical corticosteroids an effective, systemic, intermittent treatment for the long-term management of their chronic relapsing
disease.
Erythema
0 = Absent
1 = Faint erythema
2 = Prominent redness
3 = Deep intense red colour
Scaling
0 = Absent
1 = Slight flaking over limited areas, mostly fine scales
2 = Flaking over widespread area(s), coarser scales
3 = Desquamation covering over 30% of the hand,
with coarse thick scales
Lichenification hyperkeratosis
0 = Absent
1 = Mild thickening with exaggerated skin lines over limited areas
2 = Palpable thickening over widespread area(s)
3 = Prominent thickening over widespread area(s) with
exaggeration of normal skin markings
Vesiculation
0 = Absent
1 = Scattered vesicles affecting up to 10% of hand, without
erosion
2 = Scattered or clustered vesicles affecting up to 30% of hand,
without visible erosion or excoriation
3 = High density of vesicles extending over large area(s), or with
erosion or excoriation
Oedema
0 = Absent
1 = Dermal swelling over less than 10% of hands
Appendix
2 = Definite dermal swelling over more than 10% of hand

3 = Dermal swelling with skin induration over widespread area(s)
Severity assessment tools
Details of the assessment tools for measuring CHE severity in the

alitretinoin clinical trials are included below.
Fissures
0 = Absent
1 = Cracked skin affecting a small area of the hand
2 = Cracked skin affecting multiple areas of the hand and causing
pain
Physicians global assessment
The PGA provides an objective assessment of disease severity.

Using a pre-defined guide, physicians rate patients severity of
CHE according to a 5-point scale from clear to severe (Table 9).
3 = One or more deep fissures and causing bleeding or severe

pain
Pruritus pain
0 = Absent
1 = Occasional, slight discomfort a few times per day
Photographic severity guide
A recent investigation asked five experts to grade 50 photographs

of CHE, first individually, then as a consensus-building group, to
select the photographs included in the guide. Following this, a validation session with 11 different dermatologists evaluating 28
patients showed a high level of inter-rater reliability and testretest
reproducibility (Fig. 12).
Modified total lesion symptom score
The mTLSS is a composite measure of the intensity of seven

individual CHE symptoms. Scores are summed, with a maximum value of 21 (most severe disease) and a minimum of 0
(no disease). Individual symptom rating scores are provided in
Table 10.
JEADV 2010, 24 (Suppl. 3), 120
2 = Intermittent, causing discomfort frequently during the day

3 = Persistent or interfering with sleep
Conflicts of interest
TL has been working as a consultant for Basilea Pharmaceutica

International Ltd. TLD has received lecture and consultancy
fees from Basilea Pharmaceutica International Ltd. HM has
worked as a consultant for Basilea Pharmaceutica International
Ltd. JE has received lecture and consultancy fees from Basilea
Pharmaceutica International Ltd. RG-B has been reimbursed
by Basilea Pharmaceutica International Ltd. for attendance at
advisory boards; JM is an employee of Basilea Pharmaceutica
2010 The Authors

International Ltd. BH has worked as a consultant for Basilea

Pharmaceutica International Ltd. CL has been reimbursed by
Basilea Pharmaceutica International Ltd. for consultant work
as a principle investigator; PE has been reimbursed by Basilea
Pharmaceutica International Ltd. for consultant work; RB has
been a consultant and an investigator for Basilea Pharmaceutica International Ltd. The presented work has been supported by a research grant from Basilea Pharmaceutica
International Ltd.
References
1 Meding B, Wrangsjo K, Jarvholm B. Fifteen-year follow-up of hand
eczema: persistence and consequences. Br J Dermatol 2005; 152: 975
980.
2 Diepgen TL, Agner T, Aberer W et al. Management of chronic hand
eczema. Contact Dermatitis 2007; 57: 203210.
3 McDonald C, Wheatley M. Epidemiology of Work Related Diseases. 2nd
edn. BMJ Books, London, 2000.
4 Meding B, Jarvholm B. Hand eczema in Swedish adults changes in
prevalence between 1983 and 1996. J Invest Dermatol 2002; 118: 719
723.
5 Menne T, Maibach HI. Hand Eczema. 2nd edn. CRC Press, Boca
Raton, Florida London, 2000.
6 Hogan DJ, Dannaker CJ, Maibach HI. The prognosis of contact
dermatitis. J Am Acad Dermatol 1990; 23: 300307.
7 Landow K. Hand dermatitis. The perennial scourge. Postgrad Med 1998;
103: 141152.
8 Meding B, Wrangsjo K, Jarvholm B. Fifteen-year follow-up of hand
eczema: predictive factors. J Invest Dermatol 2005; 124: 893897.
9 Rook AT, Burns TF. Rooks Textbook of Dermatology. 7th edn. Edited
by Tony B et al. Blackwell Publishing, Oxford, 2004.
10 Coenraads PJ, Van Der Walle H, Thestrup-Pedersen K et al.
Construction and validation of a photographic guide for assessing
severity of chronic hand dermatitis. Br J Dermatol 2005; 152:
296301.
11 Held E, Skoet R, Johansen JD, Agner T. The hand eczema severity
index (HECSI): a scoring system for clinical assessment of hand
eczema. A study of inter- and intraobserver reliability. Br J Dermatol
2005; 152: 302307.
12 Ruzicka T, Larsen FG, Galewicz D et al. Oral alitretinoin (9-cis-retinoic
acid) therapy for chronic hand dermatitis in patients refractory to
standard therapy: results of a randomized, double-blind, placebocontrolled, multicenter trial. Arch Dermatol 2004; 140: 14531459.
13 Spruit D, Malten KE. Epidermal water-barrier formation after stripping
of normal skin. J Invest Dermatol 1965; 45: 614.
14 Pototskii II, Diachenko EI. Gas exchange through the skin and glycolytic
processes in it in eczema. Vestn Dermatol Venerol 1967 41: 3236.
15 Frame GW, Strauss WG, Maibach HI. Carbon dioxide emission of the
human arm and hand. J Invest Dermatol 1972; 59: 155159.
16 Anjo DM, Maibach H. Transepidermal chloride flux through
hydrated skin: combination chloride electrode. Br J Dermatol 1981;
105: 3944.
17 Wilson D, Severinghaus J, Maibach H. Newborn infant and adult
transcutaneous PO2 resistance: a comparison. Arch Derm Res 1981; 271:
119125.
18 Lo JS, Oriba HA, Maibach HI, Bailin PL. Transepidermal potassium
ion, chloride ion, and water flux across delipidized and cellophane
tape-stripped skin. Dermatologica 1990; 180: 6668.
19 Dreher F, Arens A, Hostynek JJ, Mudumba S, Ademola J, Maibach HI.
Colorimetric method for quantifying human Stratum corneum removed
by adhesive-tape stripping. Acta Derm Venereol 1998; 78: 186189.
JEADV 2010, 24 (Suppl. 3), 120
19
20 Morhenn VB, Chang EY, Rheins LA. A noninvasive method for

quantifying and distinguishing inflammatory skin reactions. J Am Acad
Dermatol 1999; 41: 687692.
21 Zhai H, Maibach HI. Occlusion vs. skin barrier function. Skin Res
Technol 2002; 8: 16.
22 Marzulli FN, Zhai H, Maibach HI, Wilhelm K-P. Marzulli and
Maibachs Dermatotoxicology. 7th edn. London, Boca Raton, Florida,
CRC, 2008.
23 Gorzelanny C, Goerge T, Schnaeker EM, Thomas K, Luger TA,
Schneider SW. Atomic force microscopy as an innovative tool for
nanoanalysis of native stratum corneum. Exp Dermatol 2006; 15: 387
391.
24 Huck V, Gorzelanny C, Thomas K, Luger TA, Konig K, Schneider SW.
5D-intravital tomography as a novel tool for non-invasive in-vivo
analysis of human skin. Exp Dermatol 2009; 18: 1089.
25 Karan A, Alikhan A, Maibach HI. Toxicologic implications of
cutaneous barriers: a molecular, cellular, and anatomical overview. J
Appl Toxicol 2009; 29: 551559.
26 Meding B, Swanbeck G. Consequences of having hand eczema. Contact
Dermatitis 1990; 23: 614.
27 Cvetkovski RS, Rothman KJ, Olsen J et al. Relation between diagnoses
on severity, sick leave and loss of job among patients with occupational
hand eczema. Br J Dermatol 2005; 152: 9398.
28 van Coevorden AM. Hand eczema: clinical efficacy of interventions,
and burden of disease. Appendix 1: Comparison of economic outcomes
of oral PUVA with a portable tanning unit at home vs. hospital
administered bath PUVA in patients with CHE. 2005.
29 Diepgen T, Hieke K. Cost of illness of work-related chronic hand
eczema in Germany. Value in Health 2008; 11: A290A291.
30 Meding B. Epidemiology of hand eczema in an industrial city. Acta
Derm Venereol Suppl (Stockh) 1990; 153: 143.
31 Marks R. Practical Problems in Dermatology. 2nd edn. Martin Dunitz,
London, 1996.
32 Belsito DV, Fowler JF Jr, Marks JG Jr et al. Pimecrolimus cream 1%: a
potential new treatment for chronic hand dermatitis. Cutis 2004; 73:
3138.
33 Halpern SM, Anstey AV, Dawe RS et al. Guidelines for topical PUVA:
a report of a workshop of the British photodermatology group. Br J
Dermatol 2000; 142: 2231.
34 Thestrup-Pedersen K, Andersen KE, Menne T, Veien NK. Treatment of
hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral
acitretin. A single-blind placebo-controlled study. Acta Derm Venereol
2001; 81: 353355.
35 Granlund H, Erkko P, Eriksson E, Reitamo S. Comparison of
cyclosporine and topical betamethasone-17,21-dipropionate in the
treatment of severe chronic hand eczema. Acta Derm Venereol 1996; 76:
371376.
36 Berth-Jones J, Takwale A, Tan E et al. Azathioprine in severe adult
atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br
J Dermatol 2002; 147: 324330.
37 van Coevorden AM, Coenraads PJ, Svensson A et al. Overview of
studies of treatments for hand eczema-the EDEN hand eczema survey.
Br J Dermatol 2004; 151: 446451.
38 Nagpal S, Chandraratna RA. Recent developments in receptor-selective
retinoids. Curr Pharm Des 2000; 6: 919931.
39 Freedberg IM. Fitzpatricks Dermatology in General Medicine. 5th edn.
McGraw-Hill, Health Professions Division, New York, London, 1999.
40 Geiger JM, Hommel L, Harms M, Saurat JH. Oral 13-cis retinoic acid
is superior to 9-cis retinoic acid in sebosuppression in human beings. J
Am Acad Dermatol 1996; 34: 513515.
41 Ott F, Bollag W, Geiger JM. Oral 9-cis-retinoic acid versus 13-cisretinoic acid in acne therapy. Dermatology 1996; 193: 124126.
42 Kurie JM, Lee JS, Griffin T et al. Phase I trial of 9-cis retinoic acid in
adults with solid tumors. Clin Cancer Res 1996; 2: 287293.
2010 The Authors

20
43 Weber C, Dumont E. Pharmacokinetics and pharmacodynamics of

9-cis-retinoic acid in healthy men. J Clin Pharmacol 1997; 37:
566574.
44 Coenraads PJ, van der Wetering J, Roos B, Schmitt-Hoffmann AH.
Pharmacokinetics, efficacy and safety of alitretinoin (9-cis retinoic acid)
in moderate or severe refractory chronic hand eczema. Poster FP1620
presented at EADV 2008 in Paris.
45 Schmitt-Hoffmann AH, Roos B, Baumgaertner E et al. Alitretinoin (9cis retinoic acid): pharmacokinetic interactions between alitretinoin,
ketoconazole, simvastatin and cyclosporine A. Poster 286 presented at
EADV 2007 in Vienna.
46 Schmitt-Hoffmann A, Roos B, Kovacs P et al. Influence of food on the
pharmacokinetics of oral alitretinoin (9-cis retinoic acid; BAL4079).
Poster FP1611 presented at EADV 2008 in Paris.
47 Meller S, Lauerma AI, Kopp FM et al. Chemokine responses
distinguish chemical-induced allergic from irritant skin inflammation:
JEADV 2010, 24 (Suppl. 3), 120
48
49
50
51
memory T cells make the difference. J Allergy Clin Immunol 2007;

119: 14701480.
Ruzicka T, Lynde CW, Jemec GB et al. Efficacy and safety of oral
alitretinoin (9-cis retinoic acid) in patients with severe chronic hand
eczema refractory to topical corticosteroids: results of a randomized,
double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008;
158: 808817.
Bissonnette R, Worm M, Gerlach B et al. Successful retreatment with
alitretinoin in patients with relapsed chronic hand eczema. Br J
Dermatol 2010; 162: 420426.
Diepgen T, Maleszka R, Bissonnette R et al. An open label study of the
safety and efficacy of alitretinoin in severe refractory chronic hand
eczema. Poster 281 presented at EADV 2007 in Vienna.
Diepgen TL, Elsner P, Schliemann S et al. Guideline on the
management of hand eczema ICD-10 Code: L20. L23. L24. L25. L30. J
Dtsch Dermatol Ges 2009; 7(Suppl. 3): S1S16.
2010 The Authors

This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy.
Users should refer to the original published version of the material.

Optiuni de Tratament in Eczema PDF

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Optiuni de Tratament in Eczema PDF

Uploaded by

Copyright:

Available Formats

JEADV

Redefining treatment options in chronic hand eczema (CHE)

Innovaderm Research, Montreal, QC, Canada

Friedrich Schiller University, Jena, Germany

Queens Medical Centre, Nottingham, UK

University Hospitals of Leicester, Leicester, UK

Heinrich-Heine-University, Dusseldorf, Germany

University Clinics Munster, Munster, Germany

Lynderm Research, Markham, ON, Canada

Basilea Pharmaceutica International Ltd, Basel, Switzerland

University of California, San Francisco, CA, USA

JEADV 2010, 24 (Suppl. 3), 120

ment of severe CHE is introduced in the following section. This

Understanding CHE and its impact

Hand eczema prevalence, epidemiology and

2010 The Authors

Redefining treatment options in chronic hand eczema (CHE)

contact with potentially damaging allergens and or irritants has

Classification and morphology

JEADV 2010, 24 (Suppl. 3), 120

from this debilitating condition by facilitating earlier and more

Chronic hand eczema

The role of the barrier function in CHE

2010 The Authors

Redefining treatment options in chronic hand eczema (CHE)

JEADV 2010, 24 (Suppl. 3), 120

Appropriately combining these simple, non-invasive, techniques

Further areas of investigation

Impact of CHE on society and the

Psychosocial burden of CHE

2010 The Authors

Redefining treatment options in chronic hand eczema (CHE)

Table 1 Psychosocial consequences of hand eczema

more frequent in service work, production and medical nursing

Handicap in leisure activities

Change in daily activities

Economic burden of CHE

The impact of any disease on society is felt through economic loss,

are important organs of communication and expression. Any

Occupational burden of CHE

JEADV 2010, 24 (Suppl. 3), 120

Impact of CHE on the patient

Domestic impact of CHE

2010 The Authors

Redefining treatment options in chronic hand eczema (CHE)

Benefits and limitations of current

Photochemotherapy (PUVA): Photochemotherapy can be useful

All of these factors, combined with a potentially increased fiscal

Chronic hand eczema is a disease with a multifactorial aetiology

1. Education and non-pharmacological methods

JEADV 2010, 24 (Suppl. 3), 120

The off-licence use of systemic treatments has been reported, but

2010 The Authors

Redefining treatment options in chronic hand eczema (CHE)

radiation and systemic immunosuppressants. Of the 90 studies,

Toctino (oral alitretinoin) a new

JEADV 2010, 24 (Suppl. 3), 120

There are two structurally distinct families of nuclear receptors

2010 The Authors

Redefining treatment options in chronic hand eczema (CHE)

Like all retinoids, alitretinoin is a strong teratogen and strict

Toctino (oral alitretinoin) explaining